During the last four decades, interest in fluorinated purine and pyrimidine derivatives has grown, driven by their potential use as anti-cancer and anti-viral agents and the unique properties displayed by fluorine-substituted bioactive molecules. In terms of size, replacement of hydrogen for fluorine would produce minimum stearic perturbations upon the binding of the analogue molecules to receptors or enzymes. Fluorine has a small van der Waals radius (1.35.ANG.), which closely resembles that of hydrogen (1.2.ANG.). However, the strong electron-withdrawing properties of fluorine may substantially, yet in a predictable manner, alter the chemical stability or enzymatic activity of substrate molecules. In addition, the carbon-fluorine bond is energetically more stable than the carbon-hydrogen bond.
Although the fluorine atom has been successfully introduced at the 2- and 6-positions of the purine ring system and the sugar moiety of related nucleosides, access to 8-fluoropurines and derivatives has remained limited. The absence of successful syntheses of 8-fluoropurines using elemental fluorine is quite conspicuous, as other halogens--chlorine, iodine, and particularly bromine--have been successfully used in their elemental form to produce regiospecific substitution of the C(8)-hydrogen of purines. Indeed, in many instances, the use of elemental halogen has been the most convenient procedure for regiospecific C(8)-halogen substitution.
Earlier approaches to 8-fluoropurines have been limited to a few reports, involving nucleophilic displacements, Schiemann reactions, halogen exchange reactions, and electrochemical oxidations. None of the synthetic methods involve the use of elemental fluorine or similar agents (e.g., acetyl hypofluorite) that have been successfully used in the synthesis of substituted and unsubstituted 5-fluorouracil and 5-fluorocytosine. Indeed, an attempted fluorination of an oxopurine with phosphoryl fluoride was unsuccessful.
Because of the burgeoning interest in fluorine-substituted bioactive molecules and the numerous failed attempts of others, a need exists for an effective, straightforward synthetic method for making 8-fluoropurines and related derivatives, such as 8-fluoroguanine and 8-fluoropurinylnucleosides.